肝星状细胞特异性Kcnma1缺失通过上调双调蛋白分泌减轻代谢功能障碍相关脂肪性肝病进展。
Hepatic stellate cell-specific Kcnma1 deletion mitigates metabolic dysfunction-associated steatotic liver disease progression via upregulating Amphiregulin secretion.
作者信息
Zou Yunhan, Wu Jiaoxiang, Cheng Sheng, Cheng Daqing, Chen Taoying, Guo Xirong, Tang Li, Su Xianbin, Zhang Man, Zhang Xin, Liu Ying, Zhang Jin, Bao Qun, Hou Shangwei, Sun Peng, Li Yong, Han Bo
机构信息
Hongqiao International Institute of Medicine, Tongren Hospital and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China; Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
出版信息
Mol Metab. 2025 Jul;97:102164. doi: 10.1016/j.molmet.2025.102164. Epub 2025 May 8.
OBJECTIVE
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern, with limited effective treatments. KCNMA1 potassium channel has been implicated in the pathogenesis of various metabolic diseases. However, whether and how KCNMA1 regulates MASLD have been elusive.
METHODS
Global, hepatic stellate cells (HSCs)-specific, and hepatocyte-specific Kcnma1 knockout mice were fed either a standard chow or a high-fat diet (HFD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, qPCR and western blotting. HSCs conditioned medium (CM) treatment hepatocytes experiment model and three-dimensional (3D) hepatocytes-HSCs spheroids were employed to study lipid accumulation in hepatocytes. A Cytokine Antibody Array was used to analyze the cytokine profile.
RESULTS
Our study demonstrated that global Kcnma1 deletion prevented diet-induced hepatic steatosis and improved insulin sensitivity. Further analyses using HSC-specific and hepatocyte-specific Kcnma1 knockout MASLD mouse models revealed that the protective effect against hepatic steatosis was predominantly mediated by Kcnma1 deletion in HSCs, rather than in hepatocytes. CM transfer experiment and 3D spheroid studies show Kcnma1 deletion effectively prevents lipid accumulation in hepatocytes. Mechanically, Kcnma1-deficient HSCs secrete Amphiregulin (AREG) to regulate lipid metabolism in hepatocytes via epidermal growth factor receptor (EGFR) signaling. Of clinical significance, AREG levels were notably reduced in the liver tissue of MASLD patients, while injection of recombinant AREG protein significantly ameliorated MASLD in mice.
CONCLUSIONS
Our study uncovers a novel mechanism in which Kcnma1 deletion in HSCs enhances AREG secretion, thereby reducing lipid accumulation in hepatocytes through the AREG/EGFR signaling, ultimately inhibiting the progression of MASLD.
目的
代谢功能障碍相关脂肪性肝病（MASLD）是一个日益引起全球健康关注的问题，有效治疗方法有限。钾通道蛋白1（KCNMA1）已被证明与多种代谢性疾病的发病机制有关。然而，KCNMA1是否以及如何调节MASLD尚不清楚。
方法
对全身、肝星状细胞（HSCs）特异性和肝细胞特异性Kcnma1基因敲除小鼠分别给予标准饲料或高脂饮食（HFD）。收集血清和肝脏组织，通过生化分析、组织学、qPCR和蛋白质印迹法进行分析。采用HSCs条件培养基（CM）处理肝细胞实验模型和三维（3D）肝细胞-HSCs球体研究肝细胞中的脂质积累。使用细胞因子抗体阵列分析细胞因子谱。
结果
我们的研究表明，全身Kcnma1基因缺失可预防饮食诱导的肝脂肪变性并改善胰岛素敏感性。使用HSC特异性和肝细胞特异性Kcnma1基因敲除的MASLD小鼠模型进行的进一步分析表明，对肝脂肪变性的保护作用主要由HSCs中Kcnma1基因缺失介导，而非肝细胞中的缺失。CM转移实验和3D球体研究表明，Kcnma1基因缺失可有效预防肝细胞中的脂质积累。机制上，缺乏Kcnma1的HSCs分泌双调蛋白（AREG），通过表皮生长因子受体（EGFR）信号传导调节肝细胞中的脂质代谢。具有临床意义的是，MASLD患者肝组织中AREG水平明显降低，而注射重组AREG蛋白可显著改善小鼠的MASLD。
结论
我们的研究揭示了一种新机制，即HSCs中Kcnma1基因缺失增强AREG分泌，从而通过AREG/EGFR信号传导减少肝细胞中的脂质积累，最终抑制MASLD的进展。
Zotero 插件